The present invention relates to a novel crystalline disodium pamidronate hydrate and a process for preparing it. More particularly, the present invention relates to the novel crystalline disodium pamidronate 3xcx9c4 hydrate. The present crystalline disodium pamidronate 3xcx9c4 hydrate can be obtained by the following procedures: Disodium pamidronate is obtained after neutralizing pamidronic acid (3-amino-1-hydroxypropane-1,1-diphosphonate) in a solvent with sodium hydroxide and by drying the product which is filtered from reaction mixture. The disodium salt is dissolved in water insoluble material is filtered and the filtrate is allowed to stand with stirring in room temperature to form crystals. This present invention is concerned about the synthetic method of the crystalline disodium pamidronate hydrate, by drying the crystals at the temperature of 75xcx9c85xc2x0 C. and at normal pressure including hydrate percentage of 17.0xcx9c20.0 and represented by the following formula I exists in the form of mixture of 3 hydrate and 4 hydrate. 
Pamidronic acid and its salt are known compounds and have activities against skeleton symptoms and arthritis symptoms, when orally administered. Various studies have been being carried out on the preparation of the compounds. In particular, there are reports that according to the descriptions of pamidronic acid or disodium salt prepared finally, the stabilites of proceedings for the preparation comprising them and of storage are become different greatly.
Prior Arts are as followed about the synthetic method of disodium pamidronate.
Argentine Patent No. 200,473 disclosed 2 steps of procedures is consist that the proceedings of reacting xcex2-alanine with phosphorus compound(for example, phosphorus acid, phosphorus trichloride, phosphorus oxychloride) to obtain pamidronic acid and that the proceedings of by neutralizing an obtained pamidronic acid with sodium hydroxide, cooling the reaction mixture, or by adding water, methanol, ethanol or acetone to obtain the precipitates in the reaction mixture, besides German Patent Laid-open Publication No. 2,443,963 disclosed the precedures of obtaining sodium salt by completely neutralizing or partially neutralizing pamidronic acid with sodium hydroxide to obtain salt thereof.
However, it has been known that by common neutralizing methods disodium pamidronate was obtained in a hygroscopic form lacking in crystallinity. Thus, non-crystalline materials, which absorb water in various amounts by the action of environmental humidity, are produced. In practice, it has been found that when disodium pamidronate is produced under various conditions for neutralization and working-up procedures, several different solid forms may be produced as identified according to the analysis of X-ray diffraction pattern or IR spectrum.
In case of the salt compounds in the form of multi-hydrates, there are some problems that it is extremely difficult to formulate into preparations suitable for oral administration and further more, to be decreased the stability during storage.
Meanwhile. U.S. Pat. No. 4,711,880 (corresponding to Korean Patent Publication No. 94-817) discloses the process for preparing crystalline disodium pamidronate wherein the crystals obtained from an aqueous solution of disodium pamidronate or a reaction solution of neutralization of pamidronic acid with sodium hydroxide are dried either at room temperature or at somewhat elevated temperature. In the above patent, although it is described that the formation of crystals is initiated at over 50xc2x0 C. and the drying procedure is carried out at room temperature or somewhat elevated temperature to obtain disodium pamidronate containing water of crystallization and having a good storage stability, the basic inventive concept is regarded merely as utilizing the method of the above mentioned Argentine Pat. No. 200,473. In addition, it has been described that the crystals prepared according to the process of U.S. Pat. No. 4,711,880 has the water content from 24.1 to 24.5 wt % approximately, which corresponds to about 5 moles of water per one mole of disodium pamidronate molecule, to be obtained in the form of a pentahydrate as identified by crystallography.
However, although such disodium pamidronate pentahydrate guarantees a certain degree of stability, it does not secure complete stability as yet and thus, can be used only as injectable formulations. Therefore, its use as common oral formulations such as capsules is practically difficult.
Thus, the present inventors have tried to establish the means capable for preparing disodium pamidronate hydrate which have a better storage stability and are easy to be formulated into pharmaceutical preparations.
As a result, we have found that the crystal of hydrate in the more stable state, as compared with the prior crystals, can be obtained by a process which comprises neutralizing pamidronic acid with a sodium compound under a certain reaction condition to obtain disodium pamidronate, filtering off the impurities, dissolving the resulting salt in water, allowing the resulting solution to stand at room temperature to induce the crystallization and then drying the resulting crystals at about 80xc2x0 C. to obtain the crystals of disodium pamidronate hydrate including a low water content of 17.0 to 20.0 wt %, and this invention is accomplished.
Therefore, the purpose of the present invention is to provide the crystalline disodium pamidronate hydrate having a water content of 17.0 to 20.0 wt % in the form of the mixture of crystals of trihydrate and tetrahydrate of disodium pamidronate in view of crystallography and a process for preparation thereof.
The present invention provides disodium pamidronate hydrate as characterized by a crystalline disodium pamidronate hydrate having water content of 17.0-20.0 wt % in the form of the mixture of crystals of trihydrate and tetrahydrate of disodium pamidronate in view of crystallography.
Disodium pamidronate hydrate according to the present invention has the water content different from that in the prior art. The process for preparation of such disodium pamidronate hydrate can be generally divided into the two groups consisting of a method utilizing sodium hydroxide and a method utilizing an organic sodium compound, as follows.
In the process for preparing crystalline disodium pamidronate from the reaction solution for neutralization of pamidronic acid with sodium hydroxide according to the first method, it is characterized to be included the process which pamidronic acid is neutralized with sodium hydroxide at about 90xc2x0 C. in the range of pH 7.5xcx9c8.5: the insoluble materials produced after neutralization is filtered: an alcohol is added to the filtrate to produce a salt: the resulting salt is dissolved in water and is allowed to stand at room temperature to induce crystallization: the resulting crystallizing solution is cooled to obtain the crystals: and then the resulting crystals are dried at the temperature of 75xcx9c85xc2x0 C. under normal pressure to obtain the crystalline disodium pamidronate hydrate.
In the process for preparing crystalline disodium pamidronate from the reaction solution of neutralization of pamidronic acid with an organic sodium compound according to the second method, it is characterized to be included the process which pamidronic acid is neutralized with sodium methoxide or sodium ethoxide in absolute methanol or absolute ethanol under refluxing: the salt produced from neutralization is dissolved in water and the insoluble materials produced are filtered: the filtrate is allowed to stand at room temperature to induce crystallization: the resulting solution is slowly cooled and filtered to obtain the crystals: and then the resulting crystals are dried at temperature of 75xcx9c85xc2x0 C. under normal pressure to obtain the crystalline disodium pamidronate hydrate.